An insatiable appetite, in conjunction with a low metabolic rate, means that obesity and all of its associated health risks are common in people with Prader-Willi syndrome. Overeating is one of the main barriers to independent living in adults with PWS. Moreover, attempts to control their food intake often lead to exacerbation of behavioral problems. Appetite suppression per se is unlikely to be an effective treatment for obesity in PWS, because in order to remain weight-stable these people must eat substantially less than unaffected individuals. Thus there is an urgent need for treatments that not only reduce appetite and food intake in subjects with PWS, but also increase their reduced metabolic rate. This project will determine whether two naturally derived hormones or analogues of them, could be used to treat excessive hunger and obesity in people with PWS. These hormones, called peptide YY (PYY 3-36) and pancreatic polypeptide (PP), are naturally secreted from the gastrointestinal tract, and have been shown to reduce food intake and body weight in short term studies. Our work will determine whether long-term administration of PYY 3-36 could effectively reduce food intake and body weight, by investigation of our genetically engineered mouse line, which produces excessive amounts of PYY 3-36. This is an important aim, because people with PWS are likely to need long-term treatments for weight management. We will also determine whether PYY 3-36, either alone or in combination with PP, is able to increase metabolic rate, an important consideration for effective treatment of obesity in PWS. Identification of the specific Y-receptors which mediate the weight-loss effects of PYY 3-36 or PP, will help for the development of potential orally active pharmaceuticals.